Association of celiac disease genetic markers with reproduction disorders

Cover Page

Cite item

Abstract

Background: Numerous studies have shown a link between genes involved in the immune response and infertility and miscarriage. The most significant associations have been established for the cytokine genes (IL1B, IL6, IL10, IL18), chemokine genes (CXCL9, CXCL10, CXCL11), and genes of the major histocompatibility complex HLA II class (DQA1, DQB1, DRB1). HLA genes are associated with celiac disease, a genetically determined autoimmune disorder, where male and female reproduction impairment is one of the symptoms. Aim: To assess the prevalence of polymorphic variants of the immune response genes (HLA: DQA1 DQB1, DRB1; TNF, IL10, CXCL10) in patients with reproduction disorders. Materials and methods: This pilot study involved assessment of the following gene polymorphisms: IL10 (rs1800872), TNF (rs1800629), CXCL10 (rs4386624), and HLA class II (DQA1, DQB1, DRB1) in couples (n = 220) with reproduction disorders (infertility and miscarriage). Genotyping was performed by real-time polymerase chain reaction (PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. The genotypes and alleles population data were used for comparison with the studied variants of the genes IL10 (rs1800872), TNF (rs1800629), and CXCL10 (rs4386624). Differences in the prevalence of alleles and genotypes were assessed by χ2 test. The differences were considered significant at p < 0.05. Haplotype diversity was calculated by the Arlequin software, version 3.5.x. Results: Compared to the populational data, there was significant re-distribution of the genotypes and alleles to the TNF gene (rs1800629) variant in men with impaired reproductive functions. No differences were found for other gene variants studied. The frequency of HLA class II gene (DQA1, DQB1, DRB1) haplotypes associated with celiac disease (DQ2 and DQ8) in the study sample was 23.8%. Conclusion: The results indicate the important role of genes associated with celiac disease in the development of reproduction disorders.

About the authors

L. I. Minaycheva

Research Institute of Medical Genetics, Tomsk National Research Medical Center

Author for correspondence.
Email: larisa.minaycheva@medgenetics.ru

MD, PhD, Geneticist

3 Moskovskiy trakt ul., Tomsk, 634040, Russian Federation

+7 (913) 864 61 71

Russian Federation

E. Yu. Bragina

Research Institute of Medical Genetics, Tomsk National Research Medical Center

Email: fake@neicon.ru

PhD (in Biol.), Senior Research Fellow, Population Genetics Laboratory

10 Naberezhnaya reki Ushayki ul., Tomsk, 634050, Russian Federation

Russian Federation

I. Zh. Zhalsanova

Research Institute of Medical Genetics, Tomsk National Research Medical Center

Email: fake@neicon.ru

Postgraduate Student, Population Genetics Laboratory

10 Naberezhnaya reki Ushayki ul., Tomsk, 634050, Russian Federation

Russian Federation

N. A. Chesnokova

Research Institute of Medical Genetics, Tomsk National Research Medical Center

Email: fake@neicon.ru

Resident

10 Naberezhnaya reki Ushayki ul., Tomsk, 634050, Russian Federation

Russian Federation

A. V. Marusin

Research Institute of Medical Genetics, Tomsk National Research Medical Center

Email: fake@neicon.ru

PhD (in Biol.), Research Fellow, Evolutionary Genetics Laboratory

10 Naberezhnaya reki Ushayki ul., Tomsk, 634050, Russian Federation

Russian Federation

References

  1. Паскарь СС, Боярский КЮ. Эпидемиологические аспекты бесплодного брака (обзор литературы). Проблемы репродукции. 2017;23(5): 23–6. doi: 10.17116/repro201723523-26.
  2. Здравоохранение в России. 2017: Статистический сборник. М.: Росстат; 2017. 170 с.
  3. El Hachem H, Crepaux V, May-Panloup P, Descamps P, Legendre G, Bouet PE. Recurrent pregnancy loss: current perspectives. Int J Womens Health. 2017;9:331–45. doi: 10.2147/IJWH.S100817.
  4. Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98(5): 1103–11. doi: 10.1016/j.fertnstert.2012.06.048.
  5. Gupta B, Singh P. The evolving role of genetics in recurrent pregnancy loss. In: Mehta S, Gupta B, editors. Recurrent pregnancy loss. Singapore: Springer; 2018. p. 67–77.
  6. Robberecht C, Pexsters A, Deprest J, Fryns JP, D'Hooghe T, Vermeesch JR. Cytogenetic and morphological analysis of early products of conception following hystero-embryoscopy from couples with recurrent pregnancy loss. Prenat Diagn. 2012;32(10): 933–42. doi: 10.1002/pd.3936.
  7. Tur-Torres MH, Garrido-Gimenez C, Alijotas-Reig J. Genetics of recurrent miscarriage and fetal loss. Best Pract Res Clin Obstet Gynaecol. 2017;42:11–25. doi: 10.1016/j.bpobgyn.2017.03.007.
  8. Баранов ВС, ред. Генетический паспорт – основа индивидуальной и предиктивной медицины. СПб.: Н-Л; 2009. 528 с.
  9. Pereza N, Ostojić S, Kapović M, Peterlin B. Systematic review and meta-analysis of genetic association studies in idiopathic recurrent spontaneous abortion. Fertil Steril. 2017;107(1): 150–9.e2. doi: 10.1016/j.fertnstert.2016.10.007.
  10. Shi X, Xie X, Jia Y, Li S. Maternal genetic polymorphisms and unexplained recurrent miscarriage: a systematic review and meta-analysis. Clin Genet. 2017;91(2): 265–84. doi: 10.1111/cge.12910.
  11. Tersigni C, D'Ippolito S, Di Nicuolo F, Marana R, Valenza V, Masciullo V, Scaldaferri F, Malatacca F, de Waure C, Gasbarrini A, Scambia G, Di Simone N. Recurrent pregnancy loss is associated to leaky gut: a novel pathogenic model of endometrium inflammation? J Transl Med. 2018;16(1): 102. doi: 10.1186/s12967-018-1482-y.
  12. D'Ippolito S, Gasbarrini A, Castellani R, Rocchetti S, Sisti LG, Scambia G, Di Simone N. Human leukocyte antigen (HLA) DQ2/DQ8 prevalence in recurrent pregnancy loss women. Autoimmun Rev. 2016;15(7): 638–43. doi: 10.1016/j.autrev.2016.02.009.
  13. Saccone G, Berghella V, Sarno L, Maruotti GM, Cetin I, Greco L, Khashan AS, McCarthy F, Martinelli D, Fortunato F, Martinelli P. Celiac disease and obstetric complications: a systematic review and metaanalysis. Am J Obstet Gynecol. 2016;214(2): 225–34. doi: 10.1016/j.ajog.2015.09.080.
  14. Лазебник ЛБ, Ткаченко ЕИ, Орешко ЛС, Ситкин СИ, Карпов АА, Немцов ВИ, Осипенко МФ, Радченко ВГ, Федоров ЕД, Медведева ОИ, Селиверстов ПВ, Соловьева ЕА, Шабанова АА, Журавлева МС. Рекомендации по диагностике и лечению целиакии взрослых. Экспериментальная и клиническая гастроэнтерология. 2015;(5): 3–12.
  15. Admou B, Essaadouni L, Krati K, Zaher K, Sbihi M, Chabaa L, Belaabidia B, Alaoui-Yazidi A. Atypical celiac disease: from recognizing to managing. Gastroenterol Res Pract. 2012;2012:637187. doi: 10.1155/2012/637187.
  16. Sollid LM, Thorsby E. HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis. Gastroenterology. 1993;105(3): 910–22. doi: 10.1016/0016-5085(93)90912-V.
  17. Polvi A, Arranz E, Fernandez-Arquero M, Collin P, Mäki M, Sanz A, Calvo C, Maluenda C, Westman P, de la Concha EG, Partanen J. HLA-DQ2-negative celiac disease in Finland and Spain. Hum Immunol. 1998;59(3): 169–75. doi: 10.1016/S0198-8859(98)00008-1.
  18. Barisani D, Ceroni S, Meneveri R, Cesana BM, Bardella MT. IL-10 polymorphisms are associated with early-onset celiac disease and severe mucosal damage in patients of Caucasian origin. Genet Med. 2006;8(3): 169–74. doi: 10.109701.gim.0000204464.87540.39.
  19. de la Concha EG, Fernández-Arquero M, Vigil P, Rubio A, Maluenda C, Polanco I, Fernandez C, Figueredo MA. Celiac disease and TNF promoter polymorphisms. Hum Immunol. 2000;61(5): 513–7. doi: 10.1016/S0198-8859(99)00187-1.
  20. Garrote JA, Arranz E, Tellería JJ, Castro J, Calvo C, Blanco-Quirós A. TNF alpha and LT alpha gene polymorphisms as additional markers of celiac disease susceptibility in a DQ2-positive population. Immunogenetics. 2002;54(8): 551–5. doi: 10.1007/s00251-002-0498-9.
  21. Bondar C, Araya RE, Guzman L, Rua EC, Chopita N, Chirdo FG. Role of CXCR3/CXCL10 axis in immune cell recruitment into the small intestine in celiac disease. PLoS One. 2014;9(2):e89068. doi: 10.1371/journal.pone.0089068.
  22. Bragde H, Jansson U, Fredrikson M, Grodzinsky E, Söderman J. Celiac disease biomarkers identified by transcriptome analysis of small intestinal biopsies. Cell Mol Life Sci. 2018;75(23): 4385–401. doi: 10.1007/s00018-018-2898-5.
  23. Tersigni C, Castellani R, de Waure C, Fattorossi A, De Spirito M, Gasbarrini A, Scambia G, Di Simone N. Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms. Hum Reprod Update. 2014;20(4): 582–93. doi: 10.1093/humupd/dmu007.
  24. Khashan AS, Henriksen TB, Mortensen PB, McNamee R, McCarthy FP, Pedersen MG, Kenny LC. The impact of maternal celiac disease on birthweight and preterm birth: a Danish population-based cohort study. Hum Reprod. 2010;25(2): 528–34. doi: 10.1093/humrep/dep409.
  25. Farthing MJ, Rees LH, Edwards CR, Dawson AM. Male gonadal function in coeliac disease: 2. Sex hormones. Gut. 1983;24(2): 127–35. doi: 10.1136/gut.24.2.127.
  26. Farthing MJ, Rees LH, Dawson AM. Male gonadal function in coeliac disease: III. Pituitary regulation. Clin Endocrinol (Oxf ). 1983;19(6): 661–71. doi: 10.1111/j.1365-2265.1983.tb00043.x.
  27. Ebisch IM, Pierik FH, DE Jong FH, Thomas CM, Steegers-Theunissen RP. Does folic acid and zinc sulphate intervention affect endocrine parameters and sperm characteristics in men? Int J Androl. 2006;29(2): 339–45. doi: 10.1111/j.1365-2605.2005.00598.x.
  28. Wallock LM, Tamura T, Mayr CA, Johnston KE, Ames BN, Jacob RA. Low seminal plasma folate concentrations are associated with low sperm density and count in male smokers and nonsmokers. Fertil Steril. 2001;75(2): 252–9. doi: 10.1016/S0015-0282(00)01697-6.
  29. Ebisch IM, Thomas CM, Peters WH, Braat DD, Steegers-Theunissen RP. The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Hum Reprod Update. 2007;13(2): 163–74. doi: 10.1093/humupd/dml054.
  30. Zugna D, Richiardi L, Akre O, Stephansson O, Ludvigsson JF. A nationwide population-based study to determine whether coeliac disease is associated with infertility. Gut. 2010;59(11): 1471–5. doi: 10.1136/gut.2010.219030.
  31. Ciacci C, De Rosa A, de Michele G, Savino G, Squillante A, Iovino P, Sabbatini F, Mazzacca G. Sexual behaviour in untreated and treated coeliac patients. Eur J Gastroenterol Hepatol. 1998;10(8): 649–51.
  32. Kotze LM. Gynecologic and obstetric findings related to nutritional status and adherence to a gluten-free diet in Brazilian patients with celiac disease. J Clin Gastroenterol. 2004;38(7): 567–74. doi: 10.1097/01.mcg.0000131720.90598.6a.
  33. Брагина ЕЮ, Фрейдин МБ, Бабушкина НП, Гараева АФ, Колоколова ОВ, Жалсанова ИЖ, Пузырев ВП. Анализ генов цитокиновой сети в развитии «обратной» коморбидности для бронхиальной астмы и туберкулеза. Медицинская генетика. 2017;16(1): 20–4.
  34. Самгина ТА, Бушуева ОЮ, Иванов ВП, Солодилова МА, Назаренко ПМ, Полоников АВ. Связь промоторного полиморфизма -308G / A гена фактора некроза опухоли с тяжестью течения острого панкреатита у русской популяции жителей Курской области. Экспериментальная и клиническая гастроэнтерология. 2014;(9): 17–20.
  35. Excoffier L, Lischer HE. Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows. Mol Ecol Resour. 2010;10(3): 564–7. doi: 10.1111/j.1755-0998.2010.02847.x.
  36. Khan S, Mandal RK, Jawed A, Dar SA, Wahid M, Panda AK, Areeshi MY, Ahmed Khan ME, Haque S. TNF-α -308 G > A (rs1800629) polymorphism is associated with celiac disease: A meta-analysis of 11 case-control studies. Sci Rep. 2016;6:32677. doi: 10.1038/srep32677.
  37. Fan W, Maoqing W, Wangyang C, Fulan H, Dandan L, Jiaojiao R, Xinshu D, Binbin C, Yashuang Z. Relationship between the polymorphism of tumor necrosis factor-α-308 G>A and susceptibility to inflammatory bowel diseases and colorectal cancer: a meta-analysis. Eur J Hum Genet. 2011;19(4): 432–7. doi: 10.1038/ejhg.2010.159.
  38. Lahat N, Shapiro S, Karban A, Gerstein R, Kinarty A, Lerner A. Cytokine profile in coeliac disease. Scand J Immunol. 1999;49(4): 441–6. doi: 10.1046/j.1365-3083.1999.00523.x.
  39. Nedwin GE, Naylor SL, Sakaguchi AY, Smith D, Jarrett-Nedwin J, Pennica D, Goeddel DV, Gray PW. Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization. Nucleic Acids Res. 1985;13(17): 6361–73. doi: 10.1093/nar/13.17.6361.
  40. Suh JH, Gong EY, Hong CY, Park E, Ahn RS, Park KS, Lee K. Reduced testicular steroidogenesis in tumor necrosis factor-alpha knockout mice. J Steroid Biochem Mol Biol. 2008;112(1–3): 117–21. doi: 10.1016/j.jsbmb.2008.09.003.
  41. Масленникова СО, Концевая ГВ, Золотых МА, Анисимова МВ, Феофанова НА, Мошкин МП, Недоспасов СА, Герлинская ЛА. Репродуктивные эффекты нокаута гена фактора некроза опухолей (TNF) у мышей. Вавиловский журнал генетики и селекции. 2015;19(4): 404–9. doi: 10.18699/VJ15.052.
  42. Eisermann J, Register KB, Strickler RC, Collins JL. The effect of tumor necrosis factor on human sperm motility in vitro. J Androl. 1989;10(4): 270–4. doi: 10.1002/j.1939-4640.1989.tb00100.x.
  43. Koçak I, Yenisey C, Dündar M, Okyay P, Serter M. Relationship between seminal plasma interleukin-6 and tumor necrosis factor alpha levels with semen parameters in fertile and infertile men. Urol Res. 2002;30(4): 263–7. doi: 10.1007/s00240-002-0269-y.
  44. Tronchon V, Vialard F, El Sirkasi M, Dechaud H, Rollet J, Albert M, Bailly M, Roy P, Mauduit C, Fenichel P, Selva J, Benahmed M. Tumor necrosis factor-alpha -308 polymorphism in infertile men with altered sperm production or motility. Hum Reprod. 2008;23(12): 2858–66. doi: 10.1093/humrep/den277.
  45. Khademi Bami M, Dehghan Tezerjani M, Montazeri F, Ashrafzadeh Mehrjardi HR, Ghasemi-Esmailabad S, Sheikhha MH, Kalantar SM. Tumor Necrosis Factor Alpha -308 G/A Single Nucleotide Polymorphism and Risk of Sperm Abnormalities in Iranian Males. Int J Fertil Steril. 2017;11(2): 112–6. doi: 10.22074/ijfs.2017.4830.
  46. Mauduit C, Besset V, Caussanel V, Benahmed M. Tumor necrosis factor alpha receptor p55 is under hormonal (follicle-stimulating hormone) control in testicular Sertoli cells. Biochem Biophys Res Commun. 1996;224(3): 631–7. doi: 10.1006/bbrc.1996.1077.
  47. Liu RX, Wang Y, Wen LH. Relationship between cytokine gene polymorphisms and recurrent spontaneous abortion. Int J Clin Exp Med. 2015;8(6): 9786–92.
  48. Lee BE, Jeon YJ, Shin JE, Kim JH, Choi DH, Jung YW, Shim SH, Lee WS, Kim NK. Tumor necrosis factor-α gene polymorphisms in Korean patients with recurrent spontaneous abortion. Reprod Sci. 2013;20(4): 408–13. doi: 10.1177/1933719112459237.
  49. Li S, Wang L, Xing Z, Huang Y, Miao Z. Expression level of TNF-α in decidual tissue and peripheral blood of patients with recurrent spontaneous abortion. Cent Eur J Immunol. 2017;42(2): 156–60. doi: 10.5114/ceji.2017.69357.
  50. Куртанов ХА, Данилова АЛ, Яковлева АЕ, Герасимова ВВ, Cаввина АД, Максимова НР. Молекулярно-генетическое исследование генов HLA II класса у больных целиакией в Якутии. Якутский медицинский журнал. 2015;(4): 5–7.
  51. Penn DJ. The scent of genetic compatibility: sexual selection and the major histocompatibility complex. Ethology. 2002;108(1): 1–21. doi: 10.1046/j.1439-0310.2002.00768.x.
  52. Wedekind C, Füri S. Body odour preferences in men and women: do they aim for specific MHC combinations or simply heterozygosity? Proc Biol Sci. 1997;264(1387): 1471–9. doi: 10.1098/rspb.1997.0204.
  53. Болдырева МН, Барцева ОБ, Курило ЛФ, Ткаченко ЭР, Алексеев ЛП, Адамян ЛВ. Связь HLA-DRB1-генотипа с репродуктивными неудачами. Проблемы репродукции. 2010;(6): 59–63.
  54. Carp HJ, Selmi C, Shoenfeld Y. The autoimmune bases of infertility and pregnancy loss. J Autoimmun. 2012;38(2–3):J266–74. doi: 10.1016/j.jaut.2011.11.016.

Supplementary files

There are no supplementary files to display.


Copyright (c) 2019 Minaycheva L.I., Bragina E.Y., Zhalsanova I.Z., Chesnokova N.A., Marusin A.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies